This invention relates to dietary supplement compositions, and more particularly relates to dietary supplement compositions, which promote the ability of the human body to engender calmative conditions when subjected to induced anxiety and panic due to benzodiazepine withdrawal.
As is understood by those skilled in the art, neuroregulators are chemicals that enable messages to be transmitted among nerve cells located in the brain. Each of the several neuroregulators found in the brain transmit to a specific receptor site located throughout the human body. Such neuroregulators may be either neurotransmitters that act through synaptic transmission or neuromodulators that act through mechanisms other than synaptic transmission. For instance, responsive to stress, B-endorphin has been observed in the art to be secreted concomitantly with ACTH. Similarly, leu-enkaphalin has been observed to function as a neurotransmitter in the area of the brain involved with a reward and a sense of euphoria. As will be understood by those conversant in the art, endorphins, enkaphalins, and kappa antagonists comprise endogenous opioids—which are intertwined with the body's ability to cope with stress and other equilibrium-threats.
U.S. Pat. No. 4,439,452 teaches that enkephalins have the ability to act as analgesics when administered to various animals and humans by certain special procedures, including intracerebral injections. Only limited results have been obtained from oral administration of enkephalins, however, attributable to the destruction of the enkephalins by the action of certain enzymes, which resemble carboxypeptidase. These and other enzymes, which tend to deactivate enkephalin, are known collectively as “enkephalinase.”
Blum in U.S. Pat. No. 4,761,429, teaches a composition intended to inhibit the action of enkephalinase and endorphinase. Such an enkephalinase inhibitor is a substance that tends to inhibit destruction of neuropeptides and endorphins in the animal body. More particularly, D-phenylalanine or hydrocinnamic acid—including DL-phenylalanine (“DLPA”) and D-amino acids—was discovered by Blum to function as an enkephalinase inhibitor when administered as a daily dosage in range of 32 to 10,000 mg. The technique taught therein enables endorphins to be accumulated as reservoirs in regions of the nervous system and, when stressful conditions arise, for being readily dispatched from such reservoirs into the bloodstream.
A related development in the art is disclosed also by Blum, in U.S. Pat. No. 5,189,064, wherein compositions comprising an endorphinase or enkephalinase inhibitor and, optionally, a suitable precursor promote restoration of normal neurotransmitter function without side-effects. This optional precursor component may be selected from either a dopamine precursor or a serontonin precursor, a gamma-aminobutyric acid (“GABA”) precursor or an endorphinase or enkephalinase precursor. Accordingly, those skilled in the art will appreciate the potential benefits derived from interaction between neurotransmitters such as dopamine, GABA, serontonin, and norepinephrine, on the one hand, and with opioid peptides such as endorphins and enkaphalins, on the other hand. Indeed, it should be evident that compositions premised upon such ingredients as d-phenyalanine and 1-phenyalanine in conjunction with 1-glutamine are likely to be applicable in treatment protocols for reducing drug addiction and the like.
It will be understood by those skilled in the art that, to help explain the mechanisms used by the human body to contend with challenges and threats to normal emotional and ingestive behavior, a “reward cascade” model has been suggested by K. Blum, M. C. Trachtenberg, and G. P. Kozlowski. (“Cocaine Therapy: The ‘Reward Cascade’ Link,” Professional Counselor, January/February 1989 p.27.) This reward cascade model describes normal stimulations as originating in the hypothalamus and comprising a chain of the following events: (1) neurons in the hypothalamus release serotonin; (2) serotonin activates the opioid peptide methionine enkephalin; (3) methionine enkephalin is released at the substantia nigra and interacts to inhibit receptors controlling neuronal release of GABA; (4); dopamine thus released acts as the target messenger of reward; and (5) cells originating in the locus coeruleus and projecting into the hippothalamus release norepinephrine.
It should be understood by those skilled in the art that increased supply of dopamine is a by-product of inhibiting GABA activity, since the primary function of GABA is believed to control dopamine output in the ventral tegmental region. The cascade of events, when in equilibrium, provides homeostatic regulation of the extent of activity, according to this model. On the other hand, a perturbation to equilibrium causing a modification of feelings and/or behavior are/is effectuated if a neurotransmitter or neuromodulator either becomes dysfunctional or its corresponding receptor site becomes non-responsive.
It is also known that, based in significant part upon post-respective reports of millions of persons, primarily in the United States but also worldwide, that the advent of dependency on benzodiazepines has become epidemic and extremely difficult with which to deal. Furthermore, it is clear that long-term use of benzodiazepines have given rise to many unwanted effects, including memory problems, cognition problems, emotional blunting and depression, increasing anxiety, physical symptoms and dependence. This latterdependency, unfortunately, has not been recognized by the medical community and, indeed, has routinely been exacerbated by the continued prevalent prescriptive practices of physicians throughout the United States. Contrariwise, various medical organizations throughout the world, e.g., the Committee on Safety of Medicines, the Royal College of Psychiatrists—both located in the United Kingdom—have concluded and published the finding that benzodiazepines are unsuitable for long-term use and should, in general, be prescribed only for periods of 2-4 weeks.
The identical conclusory and warning language has been rendered as being integral to the “insert” literature by ethical pharmaceutical companies producing and distributing benzodiazepines. It has been found that most physicians, however, ignore these warnings, and exclusively direct energy and attention to responding to symptoms by patients' reports. As a result millions of persons have unwittingly used these medications to control various symptoms of anxiety and related conditions while, ironically, simultaneously developing a strong dependency upon the use of benzodiazepine.
Unfortunately, it has become abundantly clear from patients' reports that physicians typically have declined to assist patients gradually discontinue use of the benzodiazepines. It would appear, based upon this evidence, that physicians have not been trained to deal with withdrawal from drug dependency, especially drugs that have been prescribed in good faith and with curative intentions. Drug withdrawal reactions generally tend to mirror the drugs' initial effects; in the case of benzodiazepines, sudden cessation after chronic use may result in multiple, serious consequences. Among these consequences are insomnia and nightmares, increased muscle tension and muscle spasms, anxiety, panic attacks and seizures. As is known to practitioners in the art, these reactions are caused by abrupt nervous system adaptations that have occurred responsive to the chronic presence of the drug. Rapid removal of the drug results in rebound over-activity of all the systems, which have been damped by the benzodiazepine and are now no longer opposed. As a result of this rebound over-activity, the brain and peripheral nervous system are in a chronic state of hyperexcitability, and, consequentially, are susceptible to the deleterious impact of stress.
U.S. Pat. Nos. 5,922,361 and 6,159,506 disclose that protracted stress has been found to cause the human body to suffer from adverse physical and psychological affects. Indeed, as will be understood by those conversant in the art, stress has been implicated in the incidence of heart disease, hypertension, migraine headaches, ulcers, and depression. It will also be understood by those skilled in the art that, while each human body reacts somewhat differently to insults from stress, the changes that generally occur are similar.
For example, it is known among practitioners that, in the course of responding to stress, the human body suffers from a depletion of neuroregulators from each of the endogenous opioid system, gamma-aminobutyric acid (“GABA”) system, and serotonin system. As another example, it is also known that the neurotransmitters dopamine, enkephalin, GABA, and norepinephrine from each of the hypothalamus and hippocampus have important affects upon anxiety disorders. Similarly, serotonin is known to also have important affects upon anxiety disorders.
Anxiety disorders, of course, are disorders associated with excessive feelings of anxiousness and nervousness. As with major depressive disorder (“MDD”), anxiety disorders are more extreme cases of what are commonly experienced at various times. A person suffering from an anxiety disorder experiences anxiety to such an extent that it significantly interferes with normal functioning; the concomitant cognitive feelings of anxiety and nervousness, neurologically translate into an overly active sympathetic nervous system. In the case of Generalized Anxiety Disorder (“GAD”), these feelings of anxiousness and nervousness are constant, as is the sympathetic activation. Not only can such feelings be unpleasant, but also can have a strong negative impact upon one's physical health. Accordingly, this type of anxiety disorder can be particularly debilitating.
Panic Disorder (“PD”) also includes anxious and nervous feelings, but these feelings come and go at unanticipated times. In fact, one of the defining components of GAD and PD is that the anxiety is not due directly to any specific external stimuli. The prototypical panic attack includes many physical components such as irregular heart rate, dizziness, faintness, shortness of breath, sweating and “clamminess.” All of these physical components are often associated with a general feeling of dissociation or unreality, and, in the extreme, even a feeling of impending death. A person suffering from such attacks—which come with little warning—can have significant problems in day-to-day functioning.
The treatment of anxiety disorders has developed considerably in the past 50 years. Early treatments used alcohol and barbiturates to treat anxiety, but both were associated with significant concomitant problems. This attitude and approach changed in the 1950s and 1960s, wherein the benzodiazepines were developed as effective anxiolytics. As will be appreciated by practitioners in the art, benzodiazepine-anxiolytics are still commonly used.
Benzodiazepines, work quickly and are generally well-tolerated, but may cause patients to suffer from initial sedation, ataxia, uncoordination, impaired memory and cognition; after chronic administration, they further may cause patients to suffer from physiological dependence, and thereby from withdrawal symptoms. It has been observed by practitioners that some of these adverse effects occur more frequently in older patients. Additional observations include occasional undesirable behavioral disinhibition in pediatric patients and in patients with a comorbid Cluster B Personality Disorder, e.g., patients that are antisocial, borderline, histrionic, or narcissistic.
Furthermore, people with a history of, or propensity for, alcohol or drug abuse are at risk for abusing benzodiazepines. Due to their lack of significant anti-depressant effects, these drugs are also not optimal for long-term monotherapy treatment of GAD patients or patients suffering from other anxiety disorders. As a result, there has been continual searching for new anxiolytic agents. For some anxiety disorders, tricyclic antidepressants (“TCA”s) and monoamine oxidase inhibitors (“MAOI”s) proved to be effective treatment. Unfortunately, prevalent application thereof was limited by side-effects especially during long-term therapy. During the past several years, selective serotonin re-uptake inhibitors (“SSRI”) have become primary monotherapy for anxiety disorders, being better-tolerated and affording a broader spectrum of efficacy than older agents. It will be appreciated that benzodiazepines are now recommended to patients as adjunctive treatment for anxiety disorders and as monotherapy for patients who are intolerant of or unresponsive to other agents.
It is known by those skilled in the art that the most prominent affect of benzodiazepines is anti-anxiety; accordingly, nearly all acute withdrawal symptoms are characterized by anxiety and related disorders. These symptoms include psychological and physical conditions such as hypersensitivity to sensory stimuli and perceptual disorders, i.e., feeling of motion, impressions of walls or floors tilting, sensation of walking on cotton, etc. In addition, and perhaps most debilitating, is the incidence of de-personalization, feelings of unreality, peripheral neuropathy, i.e., tingling and numbness in extremities, visual hallucinations, distortion of body image, muscle-twitching and weight-loss.
Benzodiazepines function by enhancing the binding qualities of the GABA neurotransmitter, considered by practitioners to be the major calming influence in the brain and body. This GABA neurotransmifter is found in almost every region of the brain and is formed through the activity of the enzyme glutamic acid decarboxylase (“GAD”); GAD is known to function as a catalyst for formation of GABA from glutamic acid. This synthesis of GABA has been linked to the Kreb's cycle. GAD requires vitamin B6 (pyridoxal phosphate) as a cofactor, which can be used to regulate the levels of GABA.
Following release, GABA can be taken back up or recycled by the neurons or by astrocytes. It appears that the release of GABA is also under auto-receptor control. GABA can be metabolized by a trans-amination reaction with alpha keto-glutarate, catalyzed by GABA-transaminase (“GABA-T”) to form succinic acid semi-aldehyde. Succinic acid semi-aldehyde is metabolized further to succinic acid which is also a Kreb's cycle intermediate. See FIGS. 1 and 4.
It is known in the art there are two basic GABA receptors, GABA-a and GABA-b. GABA-a is prevalent in the mammalian brain; 60-75% of all synapses in the central nervous system (“CNS”) are GABAergic. The GABA-a receptor is similar to the acetylcholine receptor since it is related to an ion channel; binding GABA to this receptor increases the permeability to chloride ions (Cl−), thereby causing hyperpolarization of the neuron. The GABA-a receptor has four basic subunits—2 alpha and 2 beta peptides—which surround a chloride channel. There are three basic binding sites on this complex: (1) GABA site; (2) benzodiazepine site per FIG. 3; and (3) the channel which is essentially a barbiturate site. Binding to the benzodiazepine site can have three affects: (1) agonism; (2) inverse agonism; or (3) antagonism.
As a result of GABA primary site-binding, in conjunction with secondary sites, being activated by benzodiazepine, chloride channels are opened thereby enabling chloride ions to enter the excitatory neuron and to reduce neuron-firing. See, FIG. 2. It will be understood that this action effects reduced excitation in the implicated system and engenders a “calming” effect upon the patient. When secondary sites are continually activated by an outside source by a drug such as a benzodiazepine, this effects a reduction in the available GABA. Thus, to be calmed, the excitatory system will require increasing amounts of secondary transmitter function which effects a benzodiazepine-dependency in order to reduce excitability or anxiety.
After release into the synapse, free GABA that does not bind to either the GABA-a or GABA-b receptor complexes can be taken up by neurons and glial cells. Four different membrane transporter proteins, known as GAT-1, GAT-2, GAT-3, and BGT-1, which differ in their distribution in the CNS, are believed to mediate the uptake of synaptic GABA into neurons and glial cells.
The GABA-a receptor subtype regulates neuronal excitability and rapid changes in fear arousal, such as anxiety, panic, and acute stress response. Drugs that stimulate GABA-a receptors, such as benzodiazepines and barbiturates, have anxiolytic and anti-seizure effects via GABA-a-mediated reduction of neuronal excitability, which effectively raises the seizure threshold. Findings that GABA-A antagonists produce convulsions in animals and that there is decreased GABA-a receptor binding in positron emission tomography (“PET”) study of patients with panic disorder support the anti-convulsant and anxiolytic effects of the GABA-a receptor. In addition, low plasma GABA has been reported by practitioners in the art in some depressed patients and may even serve as a trait marker for mood disorders.
Importantly, when benzodiazepine is withdrawn after five to seven days, a patient is often left with symptoms of generalized anxiety disorder and may even experience panic attacks. These symptoms are believed to be due to an insufficient level of transmitters prerequisite for facilitating chloride ion conductance. The neuron continues to fire the excitatory message and there are literally tens of thousands messages that are being sent simultaneously. This unabated firing of norepinepherine neurons, for example, produces the physical and psychological sensations that have been termed “anxiety.”
It will be appreciated that the issue then devolves to how to effectively manage anxiety symptoms. Although useful for treating craving disorders including cocaine addiction and the like, the approaches taught by the Blum compositions and methodology are limited to applying nutritional supplements on pro re nata basis, i.e., p.r.n. Heretofore, unknown in the art is a dietary supplement which provides the benefits of the teachings of Blum—for mitigating the adverse affects of the human body being regularly subjected to stressful assaults—on a self-regulating basis wherein a sufficient repository of neurotransmitters and the like is generally available for assuaging perturbations from normal physiological and psychological functions. That is, unlike a formal treatment program for anxiety under which medication or dietary supplements are prescribed as needed on a patient-by-patient basis, it would be advantageous for patients to enjoy the benefit of an available daily dosage of a food supplement that provides a means for routinely attenuating benzodiazepine-withdrawal-induced anxiety, and other physiological and psychological function impairments.
It will be understood that chronic benzodiazepines are inappropriate for administration in such individuals. While selective serotonin re-uptake inhibitors (“SSRI”s) and selective norepinephrine re-uptake inhibitors (“SNRI”s) can be helpful, people with substance abuse problems generally do not sufficiently benefit from these drugs. Indeed, these individuals tend to experience more side effects from antidepressants than individuals without abuse problems.
Accordingly, these limitations and disadvantages of the prior art are overcome with the present invention, wherein improved compositions are provided which are particularly useful in reducing the effects of anxiety without the necessity for prescribing medication or for providing food supplements on a p.r.n. basis.